DESCRIPTION (Taken from the applicant's abstract): With diverse research experience in ecology and genetics, the candidate will strive to become an independent and prominent genetic epidemiologist in area of osteoporosis research. Utilizing skills in statistical genetics, the candidate proposes to develop approaches in molecular and genetic epidemiology to search for genes underlying complex traits and to study genotype-by-environment (GXE) interaction. Osteoporotic fractures (OF) are a major public health problem associated with aging. Bone mineral density (BMD) is one major risk factor for OF. Multiple environmental and genetic factors underlie BMD variation and OF risk. Recent studies revealed several genes of potential importance for BMD with little consensus. Few studies investigated the interaction between genetic and environmental factors in determining BMD. Plans are proposed to: 1) investigate the importance of several significant genes in determining the susceptibilities to OF and BMD variation; 2) investigate the differential susceptibilities to deleterious smoking effects on bone for people of different genotypes (GXE interaction). We will recruit 1) 400 random healthy subjects (with smokers and nonsmokers, age 25-50) for a BMD study; 2) 800 random healthy subjects age 60-75, 400 with and 400 without OF, with both groups having smokers and nonsmokers; 3) genotype these subjects with RFLP and microsatellite markers; 4) analyze phenotype and molecular data by adjusting for covariates important for BMD variation and OF. Characterizing environmental and genetic factors and their interactions for BMD and OF is said to be essential for developing effective preventive interventions of OF. The research plan is well written and well conceived. The many strengths of the previous applications remain. In the last submission, the reviewers highlighted three weaknesses, which have been addressed in detail in the Introduction to Revised Application section. There are only a few remaining minor concerns. Five years of support are recommended with an outstanding level of enthusiasm.